This is an application for renewal of an Independent Scientist Award (KO-2) to support Dr. Donald T. Lysle's research activities. The specific aim of this award is to provide Dr. Lysle with some release time from his classroom teach responsibilities so that he can devote the majority of his time to research and the training of doctoral students and post-doctoral level fellows. The additional time will allow Dr. Lysle to enhance his range of scientific training and expertise. More specifically, Dr. Lysle will acquire skills in the development of animal models of infection suitable for the study of opioid-immune interactions. These goals will be accomplished within the framework of two existing NIDA funded projects. The first project (DA-7481), entitled Determinants of Opioid/Immune Interactions, provides the first direct comparisons of the impact of heroin, morphine, and their metabolites on immune status, as measured by alterations of inflammatory immune responses. The project assesses the effect of heroin, 6-monoacetylmorphine, the active metabolite of heroin, morphine and its major metabolites, morphine- 3beta-glucuronide, and morphine-6beta-glucuronide, on several models of inflammation. The second project (DA13371), entitled Behavioral Factors in Heroin's Effect on Nitric Oxide, will test the hypothesis that heroin induces wide-spread alterations in the in vivo expression inducible nitric oxide synthase (iNOS). The experiments establish dose- effect relationships for heroin, as well as the antagonism of those effects. The research plan also tests the hypothesis that heroin-induced alterations of iNOS production are conditional to environmental stimuli paired with drug administration, and that the effects are influenced by the manner of drug administration. The studies will determine whether heroin is differentially efficacious in altering nitric oxide production depending upon whether the drug is self-administered or passively infused which has important implications for the health consequences of heroin use. These projects provide important new information about how opioids induce alterations of inflammatory responses, including nitric oxide production. The HO-2 aw2ard will allow Dr. Lysle to achieve a major goal of integrating our knowledge about opioid-induced alterations of inflammatory responses with the clinical outcomes of models of bacterial infection. This integration will provide a unique and comprehensive understanding of the health consequences of opioid use.